Clotrimazole, a drug marketed to fight fungal infections, stops cell growth and proliferation through a chain of reactions that inhibits the start of protein translation. The drug's mechanism for blocking the creation of some proteins underscores its potential for cancer therapy, report José Halperin, associate professor of medicine at HMS, and his colleagues in the July 7 Proceedings of the National Academy of Sciences.
Following up on earlier research, Halperin found that clotrimazole arrests cellular growth by flushing calcium ions from intracellular stores. The release of these ions activates an enzyme, protein kinase R, which phosphorylates the protein eIF2-alpha. That, in turn, interferes with an energy exchange necessary to initiate a new round of protein translation. Stopping protein synthesis reduces the expression of growth-promoting cyclins A, E, and D1. Without the cyclins, cyclin dependent kinases cannot activate, and the cell is stopped from dividing.
Inhibiting the first step of translation and reducing the expression of cyclins, prevents the cell from progressing from the phase just before DNA synthesis begins, to the next step of the cell's growth and division cycle. Uncovering clotrimazole's mechanism as an anticancer drug demonstrates the potential of translation initiation as a target for cancer therapy, says first author Hussein Aktas, research associate in the Laboratory for Membrane Transport at HMS, where the research was conducted.
The surgical procedure pallidotomy has proven its ability to reduce the side effects of treating Parkinson's disease with dopamine, calming tremors and dyskinesias. About 70 percent of patients showed improvement following the surgery, announced G. Rees Cosgrove at a press seminar on "Brain and Psyche 1998." Cosgrove is an associate professor of clinical surgery (neurosurgery) at HMS and the Movement Disorders Center of Massachusetts General Hospital.
Over five years, Cosgrove treated 85 patients with pallidotomy, creating a tiny lesion in a brain structure called the globus pallidus. It is thought that the operation works by partially restoring the balance between competing neurochemical control systems in the brain. The average improvement in motor skills, according to the Clinical Global Improvement Scale, was 30 percent, with the dyskinesias almost abolished on the side of the body opposite where the lesion was created.
The ideal candidates for the treatment, says Cosgrove, develop Parkinson's in their 30s and 40s and have since developed severe drug-induced dyskinesias. Pallidotomy was originally used to treat Parkinson's in the 1940s and '50s but fell into disuse with the introduction of drug therapies. The procedure made a comeback in Europe in the 1980s as a treatment for the side effects of those therapies.
Fibrous clumps of amyloid-beta protein have long been associated with Alzheimer's disease, and now researchers have shown that the protein can directly cause brain degeneration. In the July issue of Nature Medicine, Bruce Yankner, associate professor of neurology at HMS and Children's Hospital, along with Changiz Geula, an assistant professor of medicine at HMS and Beth Israel Deaconess, report that injecting the protein into rhesus monkeys killed brain cells. The technique represents a new primate model for Alzheimer's.
In 1990 Yankner found that amyloid-beta can kill brain cells in vitro, but still had to discover whether the protein had the same effects in vivo. When studies of mice turned out inconclusive, he started looking for a new model. In the current study, he injected amyloid-beta into the brains of aged monkeys, which resulted in Alzheimer's-like brain degeneration, including neuronal loss, tau phosphorylation, and microglial proliferation. In a second part of the study, the researchers found that amyloid-beta causes more damage in old brains than young brains.
Along with providing some insight into the degenerative mechanisms of Alzheimer's, the research has created a much-needed model for studying the disease. "If we can learn why the aging brain, but not the young brain, is susceptible to the toxic effects of amyloid-beta, we may be able to target the susceptibility factor with drugs," says Yankner.
Stopping the AIDS epidemic will require the development of an effective HIV vaccine, but the approaches taken so far have had little success, says Norman Letvin, professor of medicine at HMS and Beth Israel Deaconess. In a review of progress on an HIV-1 vaccine in the June 19 Science, he suggests that researchers need to find out more about the virus and the immune response to it before they can improve their vaccination strategies.
The prospect of a live HIV vaccine similar to the one used against smallpox appears unlikely. Although such a vaccine has protected macaques from simian immunodeficiency virus (SIV) in some experiments, the long-term results have been controversial. "There is accumulating evidence in macaques that the genetic strategies that have been used to date cannot create a safe live, attenuated AIDS virus vaccine," writes Letvin. His view was echoed by the results of an experiment by Ruth Ruprecht, associate professor of medicine at HMS and Dana-Farber, presented at the recent 12th World AIDS Conference in Geneva. She found that an SIV vaccine can be deadly, with the weakened virus mutating into a disease-causing form in a significant number of vaccinated animals.
Inactivated viruses with adjuvant, a recipe similar to the vaccines that protect people against influenza and polio, have elicited a nonvirus specific response in monkeys. However, that response was to attack the cells in which the virus was cultivated, rather than the virus.
Subunit vaccines made of highly purified viral proteins hold some promise, writes Letvin. Although the National Institutes of Health canceled large-scale trials using this type of vaccine, other U.S. government agencies and private vaccine manufacturers are proceeding with trials in Thailand. The vaccine does not elicit HIV-1 specific cytotoxic T lymphocytes or generate an antibody response that can neutralize the virus. Still, he writes, this type of vaccine may be useful in conjunction with other vaccination strategies.
Inserting genes from HIV into other viruses to create a live vector-based vaccine has the potential to elicit a strong immune response. The limitation of this approach, Letvin says, is that the genes have to be small, genetically stable, and safe. Another drawback is that the viruses used to carry the gene, such as vaccinia, can create life-threatening infections in immunosuppressed people. Tinkering with the virus used to carry the genes, or even using bacteria, might be the solution, he writes.
--Cassie Ferguson
Focus 7/17/98